Trientine Tetrahydrochloride (TETA 4HCL) for the Treatment of Wilson's Disease

Inclusion Criteria:

1. Patient is able to provide, and has provided, written informed consent

2. Written documentation has been obtained in accordance with the relevant country andlocal privacy requirements, where applicable, including: For US sites: Authorizationfor Use and Release of Health Research Study Information and for EU sites: DataProtection Consent

3. Male or female, aged ≥ 18 and ≤ 75 years of age at time of consent

4. Patient has a diagnosis of Wilson's disease, as defined by a prior or currentLeipzig score of ≥ 4

5. Patient's Wilson's disease is clinically stable, in the opinion of the investigator,and being treated with penicillamine for at least 1 year (52 weeks) prior to thescreening/enrolment visit

6. Patient is on a stable dose and regimen of penicillamine for at least 4 months (16weeks) prior to the screening/enrolment visit (other prescribed treatments forWilson's disease not permitted during this study)

7. No anticipated need that patient will require additional pharmacological therapiesother than study medication, including prescribed zinc therapy, for the managementof copper levels during the study

8. Patient must be willing to maintain stable diet throughout the study, and avoidfoods with high copper content, including the Penicillamine Baseline Period

9. Patient considered suitable to receive therapy with both TETA 4HCl and penicillamineadministered twice a day

10. Negative central laboratory tests for HIV and viral hepatitis (results will beavailable after start of run-in period)

11. For female patients of childbearing potential, negative urine pregnancy test (atscreening/enrolment visit and prior to randomization)

12. For females of childbearing potential, use of a reliable form of contraceptive

13. Patient is considered as able to complete study requirements and attend the studyvisits, in the opinion of the investigator Additional inclusion criteria following receipt of Screening laboratory results

14. Patient is adequately controlled and tolerating penicillamine therapy as defined byfulfilment of all of the following: a. Serum non-ceruloplasmin bound copper (NCC)level between ≥ 25 and ≤ 150 μg/L* b. 24-hour urinary copper excretion of between ≥ 100 and ≤ 900 μg/24 hours* c. Alanine transaminase (ALT) < 2 times upper limit ofnormal* d. No other laboratory or clinical findings that would prevent continuationof maintenance therapy, in the opinion of the investigator

• Based on results from screening/enrolment visit samples for which can be takenwithin ± 7 days of visit. Result should be within the assay limits of quantificationfor the sample. The ranges in μmol of copper are 0.40 to 2.38 μmol/L for NCC and 1.59 to 14.29 for 24-hour urinary copper excretion (using division by 63 of value in μg per Walshe, 2011). In the event that one or more of the above lab values falloutside the specified range, it can be repeated, including at the Week 4 and Week 8visits. Additional inclusion criteria at Week 12 visit (end of Penicillamine BaselinePeriod) and prior to randomization

15. Patient is adequately controlled and tolerating penicillamine therapy as defined byfulfilment of all of the following criteria:

16. Serum non-ceruloplasmin bound copper (NCC) level between ≥ 25 and ≤ 150 μg/L*

17. 24-hour urinary copper excretion of between ≥ 100 and ≤ 900 μg/24 hours**

18. Alanine transaminase (ALT) < 2 times upper limit of normal*

19. No other laboratory or clinical findings that would prevent continuation ofmaintenance therapy, in the opinion of the investigator

• Based on lab values from Week 8 visit; ** Based on lab value from Week 4visit as routinely not performed at Week 8 visit, however can also bebased on value at Week 8 visit if a repeat (unscheduled) urinary copperexcretion was performed at this visit. Result should be within the assaylimits of quantification for the sample. The ranges in μmol of copper are 0.40 to 2.38 μmol/L for NCC and 1.59 to 14.29 for 24-hour urinary copperexcretion (using division by 63 of value in μg per Walshe, 2011). In theevent that one or more of the above lab values fall outside the specifiedrange, it can be repeated. The repeat value(s) must be available prior torandomization at Week 12 and, if within specified range, the patient cancontinue to randomization. If a patient fails this additional criterion atthe end of the Penicillamine Baseline Period, the patient can return tothe start of the run-in period i.e. Day 1 (but only once). A negativeurinary pregnancy test is also required prior to randomization for femalesof childbearing potential.

Exclusion Criteria:

1. Patient is in 'de-coppering' phase of treatment for Wilson's disease, in the opinionof the investigator

2. Patient evidence of uncontrolled liver disease, including but not limited to:

3. Modified Nazer score of > 4 (result may not be available until after start ofrun in period since based on lab results*)

4. decompensated cirrhosis

5. acute hemolytic anemia

6. acute hepatitis

7. hepatic malignancy

8. evidence of acute liver failure

9. Cause of patient's liver disease is due to another condition, in the investigator'sopinion

10. Patient has severe anemia defined as hemoglobin of ≤ 9 g/dL (result will beavailable after start of run-in period*)

11. Patient has experienced a gastrointestinal bleed within 6 months (24 weeks) prior toscreening/enrolment visit

12. Patient has renal impairment defined as creatinine clearance of ≤ 30 mL/min (resultmay not be available until after start of run-in period*), or patient has nephritisor nephrotic syndrome, in the opinion of the investigator

13. Patient has neurological disease that prevents swallowing of study medication (e.g.,requires a nasogastric feeding tube) or requires intensive in-patient medical care

14. Patient is currently taking medication containing trientine for management ofWilson's disease or has taken it within 4 months (16 weeks) of screening/enrolmentvisit

15. Patient is currently receiving prescribed zinc therapy for management of Wilson'sdisease or has taken it within 4 months (16 weeks) of screening/enrolment visit

16. Patient is taking any of the following concomitant therapies: gold therapy,antimalarial therapy, cytotoxic drugs, oxyphenbutazone, phenyl butazone

17. Patient has a known intolerance, allergy or sensitivity to penicillamine (that isuncontrolled) or to TETA 4HCl, including any component of the study medication

18. For female patients of childbearing potential, planning a pregnancy during studyperiod or currently nursing

19. For female patients of childbearing potential, unable or unwilling to use a reliableform of contraceptive throughout the study

20. Patient is currently participating in another therapeutic study, or has previouslyparticipated in a therapeutic study within 30 days of screening/enrolment visit (orlonger, if local requirements specify this)

21. Patient has any condition or in any situation which, in the investigator's opinion,puts the patient at significant risk, could confound study results, or may interferesignificantly with the patient's participation in the study